The subject invention pertains to compounds which are useful as anti-inflammatory agents and to compositions containing such compounds as active ingredients. More particularly, the invention concerns novel uses for biologically active bis-heterocyclic compounds, e.g. bis-indoles, and to pharmaceutical compositions containing these compounds. The novel use of the compounds relates to the anti-inflammatory properties of the disclosed bis-heterocyclic compounds. Specifically exemplified herein are the compounds identified as soritin A, HB-238, Bis(3,3xe2x80x2indolyl)methane, HB-236, 2-Bis(3,3xe2x80x2indolyl) acetaldehyde, HB-237, and their salts, analogs and derivatives.
The prevention and control of inflammation is of prime importance to man, and much research has been devoted to development of compounds having anti-inflammatory properties. Certain methods and chemical compositions have been developed which aid in inhibiting or controlling inflammation, but additional anti-inflammatory methods and compositions are needed.
Bis-heterocyclic compounds such as bis-indoles have been previously described as having antimicrobial, antitumor or antiviral activity. Specifically, the bis-indole compounds known as topsentins are disclosed in U.S. Pat. No. 4,866,084. Dragmacidin and its related compounds isolated from the marine sponge of the Dragmacidon sp. are disclosed in U.S. Pat. No. 4,970,226. These patents are herein incorporated by reference. These compounds as well as the homocarbonyl topsentins and hamacanthins have also been described as having inhibitory activity against cellular inflammatory responses. See U.S. Pat. Nos. 5,290,777 and 5,464,835 which are also hereby incorporated by reference. The present invention provides compounds having advantageous potent anti-inflammatory activity.
Other advantages and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.
The present invention provides compounds which are useful as anti-inflammatory agents. The objects of the present invention are accomplished by the provision of a novel utility for certain bis-heterocyclic compounds.
In one example, the compounds useful according to the subject invention have the following formula: 
R1-10 are the same or different selected from xe2x80x94H, xe2x80x94OH, halogen, xe2x80x94COOH, xe2x80x94COOR, C1-C8 alkyl , C1-C8 alkoxyl, mesyl, tosyl, xe2x80x94OCOR, or NZ1Z2 (wherein the Zs can be the same or different);
X1 and X2 are the same or different selected from xe2x80x94H, xe2x80x94R, xe2x80x94COY, C(NZ1)Y
Y is xe2x80x94H, xe2x80x94OH, NZ1Z2 (wherein the Z1 and Z2 can be the same or different) C1-C8 alkyl, C1-C8 alkoxyl or an amino acid linked through the amine functionality forming an amide bond;
Z1 and Z2 are the same or different and independently selected from xe2x80x94H, xe2x80x94OH, C1-C8 alkyl, C1-C8 alkoxyl or xe2x80x94COR;
R is C1-C8 alkyl, or aryl
A preferred embodiment of the subject invention pertains to the bis-indole compounds soritin A, HB-238, (I), Bis(3,3xe2x80x2indolyl)methane, HB-236, (II) and 2,2-Bis(3,3xe2x80x2indolyl) acetaldehyde, HB-237 (III).
As described herein, the invention also comprises pharmaceutical compositions, e.g. anti-inflammatory compositions, containing as an active ingredient an effective amount, preferably between about 0.1 to 45%, especially 1 to 25%, by weight based on the total weight of the composition, of one or more compounds according to the formula expressed above and a non-toxic, pharmaceutically acceptable carrier or diluent. In addition, a pharmaceutical composition can comprise at least one of the subject compounds and a second component comprising at least one other active compound. Such other active compounds include but are not limited to, anti-inflammatory compounds for example, steroidal compounds, including hydrocortisone and the like; or non-steroidal anti-inflammatories, including acetylsalicylic acid (aspirin), ibuprofen, acetaminophen, indomethacin, and the like. The second active ingredient can include antiviral, antibacterial, antifungal or other antimicrobial compounds or antitumor compounds as well.
As described herein, the invention further comprises processes for the production of compounds and compositions of the invention and novel methods of use thereof, e.g. methods of inhibition of the inflammatory response in an animal.
In accordance with the invention, methods for inhibiting inflammation comprise administering to an animal in need of such treatment an effective amount of the pharmaceutical composition.